This application is a national stage entry under 35 U.S.C. xc2xa7371 of PCT/JP98/02783, filed Jun. 23, 1998.
The present invention relates to a novel triazolo-1,4-diazepine compound having a platelet activating factor (PAF) antagonistic action and a thromboxane A2 (TxA2) synthesis inhibiting action and a pharmaceutical composition, etc. having said compound or its hydrate or its pharmaceutically acceptable salt as an active ingredient.
PAF and TxA2 interact with each other and are involved in various allergic, inflammatory, and hypersecretory diseases such as asthma, arthritis, rhinitis, bronchitis and urticaria obliterative, or circulatory ischemic diseases obstructive thrombotic diseases, arteriosclerosis, pulmonary hypertension, and further gastric ulcer, psoriasis, etc. and other conditions. Accordingly, in the treatment of these diseases, a higher therapeutic effect can be expected from simultaneously suppressing rather than individually suppressing the actions of PAF or TxA2.
In the past, as a compound simultaneously suppressing the actions of PAF and TxA2, there has been known the 1,4-dihydropyridine compound disclosed in Japanese Unexamined Patent Publication (Kokai) No. 8-40904.
On the other hand, the fact that a 1,4-diazepine compound has an anti-PAF action is described in, for example, Japanese Unexamined Patent Publication (Kokai) Nos. 2-49787, 2-191281, 2-256682, etc. However, these compounds do not have the action of simultaneously suppressing the actions of PAF and TxA2.
In view of the above circumstances, an object of the present invention is to provide a 1,4-diazepine compound which simultaneously suppresses the actions of PAF and TxA2.
The present inventors synthesized triazolo-1,4-diazepine compounds having various substituent groups and engaged in repeated studies on the actions of the compounds and, as a result, found that a triazolo-1,4-diazepine compound having the following formula (I) possesses a superior PAF antagonistic action and thromboxane A2 synthesis inhibiting action, whereby the present invention has been completed.
That is, in accordance with the present invention, there is provided a triazolo-1,4-diazepine compound having the formula (I): 
wherein A represents CO, COxe2x80x94B, or B, B represents a C1 to C6 alkylene group or a C2 to C6 alkylene group having an oxygen atom interposed in the middle thereof, X represents Nxe2x80x94O or CH, n represents an integer of 2 to 6, R represents a hydroxyl group, a C1 to C6 lower alkyloxy group or a C1 to C6 lower alkylamino group, provided that these groups may be substituted with an N,N-dimethylamino group, an N,N-diethylamino group, a phenyl group, or a heterocyclic group such as a pyridyl group, a morpholino group, a piperazino group, an imidazolyl group, and R1 represents a hydrogen atom or a C1 to C3 lower alkyl group.
In accordance with the present invention, there are further provided a pharmaceutical composition containing the compound having the formula (I) or its hydrate or its pharmaceutically acceptable salt as an active ingredient, in particular an antiallergic or antiinflammatory pharmaceutical composition.
The present invention will be explained in further detail below.
In the triazolo-1,4-diazepine compound having the formula (I), as mentioned above, A represents CO, COxe2x80x94B, or B, and B represents a C1 to C6 alkylene group or a C2 to C6 alkylene group having an oxygen atom interposed in the middle thereof. Preferably, A represents COxe2x80x94CH2, COxe2x80x94CH2OCH2, or a C1 to C4 alkylene group, in particular CH2 (methylene group). Specifically, B is preferably a methylene group, an ethylene group, a trimethylene group, a tetramethylene group, a hexamethylene group, a group (CH2OCH2) having an oxygen atom interposed between one methylene group and another methylene group, etc. X, as mentioned before, is Nxe2x80x94O or CH. Further, as mentioned above, n is an integer of 2 to 6, preferably 4. Further, R is a hydroxyl group, a C1 to C6 lower alkyloxy group, or a C1 to C6 lower alkylamino group. The above groups may be substituted with an N,N-dimethylamino group, an N,N-diethylamino group, a phenyl group, or a heterocyclic group such as a pyridyl group, a morpholino group, piperazino group, imidazolyl group etc. Preferably a C1 to C3 lower alkyloxy group (which may be substituted with an N,N-dimethylamino group, N,N-diethylamino group, pyridyl group, morpholino group, piperazino group, or imidazolyl group), particularly preferably a C1 to C3 lower alkyloxy group. R1 is a hydrogen atom or a C1 to C3 lower alkyl group, preferably a methyl group.
Among the triazolo-1,4-diazepine compounds of the present invention, specific examples of particularly preferable compounds are Compound 4, Compound 6, Compound 7, Compound 9, Compound 10, and Compound 11 described in the Examples below.
Note that the compound of the present invention may optionally, form a hydrate or salt thereof. These, of course, are included in the present invention.
The compound of the present invention is produced by ordinary methods, but the representative methods among these are as follows.
(Production Method 1) 
wherein, A, X, n, R, and R1 are as defined above, Axe2x80x2 represents a hydroxyl group, a halogen atom, a mesyloxy group, a tosyloxy group, etc.
That is, the desired compound having the formula (I) can be obtained by the condensation reaction between the compound of the formula (II) and the compound of the formula (III) in an ordinary method.
As the compound represented by the formula (III), an acid halide such as an acid chloride or acid bromide; an active ester such as N-hydroxybenzotriazole or N-hydroxysuccinimide; etc. a symmetric acid anhydride; a mixed acid anhydride such as an alkyl carbonic acid, methane sulfonic acid, or p-toluene sulfonic acid, etc. may be mentioned. The reaction in the case of using these compounds is carried out in the absence of a solvent or in the presence of a solvent which is not involved in the reaction such as toluene, xylene, chloroform, dichloromethane, tetrahydrofuran, or dimethylformamide, etc. under heating, for example, by a condensation reaction such as a dehalogenation reaction etc. In this case, a more preferable result is obtained if the reaction is carried out in the presence of an inorganic salt such as sodium hydrogencarbonate, sodium carbonate, or sodium hydroxide or an organic salt such as triethylamine, pyridine, or piperazine.
When a free carboxylic acid is used as the compound of formula (III), a more preferable result is obtained, if the reaction is carried out in the presence of a condensing agent such as dicyclohexylcarbodimide or 1,1xe2x80x2-carbonyldiimidazole etc.
When a compound containing an alkyl group to which a halide etc. or a leaving group is bonded is used, as the compound of formula (III), the reaction is carried out using an inorganic salt such as potassium carbonate, sodium carbonate, calcium carbonate, sodium hydroxide, a hydrogenated alkali metal such as sodium hydride or potassium hydride, or an organic salt such as triethylamine, pyridine, or piperazine, optionally, in the presence of a catalyst such as a crown ether etc. In particular, the reaction is suitably carried out with sodium hydride in dimethylformamide in the presence of a crown ether catalyst.
(Production Method 2)
The starting material (III) usable in the above production method 1 may be produced by, for example, the following method A or method B: 
wherein, A, A1, n, and R are the same as defined above, A2 represents a group stable under alkaline conditions such as a t-butyldiphenylsilyloxy group or t-butyldimethylsilyloxy group or a group the same as A1, and m is an integer of 3 to 7.
The above steps will be explained in brief below.
(Method A)
The compound of formula (IV) is allowed to react with hydroxylamine in an ordinary method to form an oxime, then is allowed to react, in an inert solvent, in the presence of a base, with a halogenated alkanoic acid ester such as ethyl 5-bromovalerate or a halogenated alkanoic acid amide such as N-propyl 5-bromovaleramide, etc. then the blocking group of the hydroxyl group is removed and, if desired, a treatment such as halogenation, tosylation, mesylation etc. is carried out to introduce a leaving group or oxidize the alcohol to obtain the compound of formula (V).
The preferable base usable in this reaction is a hydrogenated alkali metal or hydrogenated alkali earth metal such as sodium hydride or calcium hydride.
(Method B)
The compound of formula (IV) is allowed to react with triphenylphosphonium bromide, etc. in a solvent in the presence of a base to form a corresponding carboxylic acid, then if desired, is esterified or amidated, then the blocking group for the hydroxyl group is removed and, if desired, is treated by halogenation, tosylation, mesylation, etc., to introduce a leaving group or to oxidize the alcohol, whereby the compound of formula (VI) is formed.
The base usable in this reaction is, for example, n-butyllithium, sodium hydride, potassium t-butoxide, etc. The solvent usable in this reaction is, for example, ether, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, t-butanol, or mixed solvents thereof. The reaction is preferably carried out under an atmosphere of a dry inert gas, for example, nitrogen gas or argon gas. The reaction temperature is preferably xe2x88x9210xc2x0 C. to 80xc2x0 C., more preferably 60xc2x0 C. to 70xc2x0 C.
Further, the compound having the formula (I) may be produced from the compound of formula (II) and the compound of formula (IV) by reacting these compounds in the similar method to the above production method 1 and then the resulting compound is treated in the same way as the method A or the method B.
The compounds having formula (I) obtained by these methods may then be processed by a known processing means, for example, extraction, chromatography, recrystallization, etc. to be isolated and purified.
The compound of the formula (I) according to the present invention has an asymmetric carbon atom, and therefore, has optical isomers. The present invention includes any optical isomers and mixtures of isomers. Further, in the present invention, there are geometrical isomers, in addition to optical isomers. The present invention also includes all of these isomers and mixtures thereof. Further, the mixtures of isomers may be separated into the individual isomers, if desired, by a fractional crystallization method or chromatography etc.
The compound according to the present invention has a PAF antagonistic action and thromboxane synthesis inhibiting action, and therefore, is useful as an agent for the treatment of allergic diseases, inflammatory diseases, hypersecretory diseases, ischemic diseases, obliterative thrombotic diseases, arteriosclerosis, pulmonary hypertension, gastric ulcer, psoriasis, etc.
The compound of the present invention may be administered by a suitable administration method such as oral or parenteral administration when used as a drug for the treatment of allergic diseases or inflammatory diseases. The form of oral administration may include, for example, tablets, granules, capsules, pills, powders, etc., and further, the form of parenteral administration may include, for example, injections, inhalants, suppositories, liquid preparations, etc. These preparations may be produced by ordinary methods from the compound of the present invention or its pharmaceutically acceptable salt and a carrier.
For example, in the case of oral administration, the preparation can be prepared into the desired form using excipients such as lactose, glucose, corn starch, etc. and sucrose, disintegrants such as calcium carboxymethylcellulose and hydroxypropylcellulose, etc. lubricants such as calcium stearate, magnesium stearate, talc, polyethylene glycol, or a hydrogenated oil, etc. binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, polyvinyl alcohol, gelatin, or arabic gum, etc. humectants such as glycerol or ethylene glycol, etc. and, in addition, if necessary, surfactants, corrigents, etc. Further, in the case of a parenterally drug, diluents such as water, ethanol, glycerin, propylene glycol, polyethylene glycol, agar, or tragacanth gum etc. may be used and, in accordance with need, solubilizing agents, buffering agents, preservatives, flavors, coloring agents, etc. may be used.
When the compound of the present invention is formulated as an antiallergic, the dosage, in terms of the amount of the compound of the present invention per adult is 1 to 300 mg per day, preferably 1 to 100 mg, in the case of oral administration and 0.1 to 100 mg per day, preferably 0.5 to 30 mg, in the case of parenteral administration. The desired effect of treatment can be expected by the administration divided into one to three dosages per day.